Computational study to understand mechanism of isoniazid drug resistance caused by mutation (R268H) in NADH dehydrogenase of Mycobacterium tuberculosis
| Autor: | Shraddha Deshmukh, Lingaraja Jena, Tapaswini Nayak, Bhaskar C Harinath, Gauri Wankhade |
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| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
Mutation biology Chemistry Clinical Biochemistry Mutant Isoniazid Biomedical Engineering NADH dehydrogenase Health Informatics biology.organism_classification medicine.disease_cause Molecular biology Mycobacterium tuberculosis Enzyme Health Information Management medicine biology.protein NAD+ kinase Protein secondary structure medicine.drug |
| Zdroj: | International Journal of Bioinformatics Research and Applications. 15:243 |
| ISSN: | 1744-5493 1744-5485 |
| Popis: | NADH dehydrogenase (Ndh) of Mycobacterium tuberculosis is essential for conversion of NADH to NAD+ in the presence of FMN. An increased NADH/NAD+ ratio was reported due to mutation (R268H) in Ndh, causing INH resistance. To study the effect of this mutation on Ndh, molecular dynamics (MD) simulation analysis was performed for both wild and mutant models independently as well as for docked complexes (Ndh-NADH and Ndh-FMN). Simulation study showed that mutation (R268H) affected the secondary structure of the enzyme giving extra stability to the mutant model R268H as observed in the root mean square deviation (RMSD) plot. Furthermore, it was observed that both wild-type and mutant models of Ndh were quite stable in complex with NADH but in case of FMN, the Ndh mutant appears to be more unstable and might be the reason for decreasing NAD+ concentrations thus hindering INH-NAD adduct formation resulting in isoniazid resistance. |
| Databáze: | OpenAIRE |
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